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TitleCryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates.
Journal, issue, pagesCommun Biol, Vol. 4, Issue 1, Page 849, Year 2021
Publish dateJul 8, 2021
AuthorsJesús G Galaz-Montoya / Sarah H Shahmoradian / Koning Shen / Judith Frydman / Wah Chiu /
PubMed AbstractHuntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine (polyQ) tract in the mutant huntingtin (mHTT) protein. The formation and topology of ...Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine (polyQ) tract in the mutant huntingtin (mHTT) protein. The formation and topology of filamentous mHTT inclusions in the brain (hallmarks of HD implicated in neurotoxicity) remain elusive. Using cryo-electron tomography and subtomogram averaging, here we show that mHTT exon 1 and polyQ-only aggregates in vitro are structurally heterogenous and filamentous, similar to prior observations with other methods. Yet, we find filaments in both types of aggregates under ~2 nm in width, thinner than previously reported, and regions forming large sheets. In addition, our data show a prevalent subpopulation of filaments exhibiting a lumpy slab morphology in both aggregates, supportive of the polyQ core model. This provides a basis for future cryoET studies of various aggregated mHTT and polyQ constructs to improve their structure-based modeling as well as their identification in cells without fusion tags.
External linksCommun Biol / PubMed:34239038 / PubMed Central
MethodsEM (subtomogram averaging)
Resolution32.0 - 35.0 Å
Structure data

EMDB-21248:
Subtomogram average of filamentous segments from in vitro aggregates of mutant huntingtin exon 1 (Q51)
Method: EM (subtomogram averaging) / Resolution: 35.0 Å

EMDB-21253:
Subtomogram average of filamentous segments from in vitro aggregates of polyglutamine peptide (Q51)
Method: EM (subtomogram averaging) / Resolution: 32.0 Å

Source
  • Pichia kudriavzevii (yeast)

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